Alpha-Synuclein

The accumulation of alpha-synuclein fibrils within Lewy bodies and Lewy neurites is the defining feature of idiopathic Parkinson's disease (PD). Alpha-synuclein has been implicated in disease pathogenesis with the discovery of dominantly inherited alpha-synuclein gene (SNCA) mutations in rare familial versions of PD.

The development of dementia in PD is associated with more widespread accumulation of aggregated alpha-synuclein protein, particularly accumulation in neocortical regions responsible for higher cognitive function. Over 60% of patients with PD and dementia have widespread accumulation of a second aggregated protein, Abeta, which is a defining feature of Alzheimer's disease (AD). In AD, Abeta accumulation occurs in combination with aggregated tau protein accumulation; however, widespread tau deposition only rarely occurs in PD.

Interestingly, our recent cerebrospinal fluid (CSF) studies in people with PD indicates altered metabolism of both alpha-synuclein and Abeta. Furthermore, a correlation between decreased CSF levels of the two proteins suggests a link between changes in their metabolism. 

 

SELECT Publications

  1. Yue X, Dhavale DD, Li J, Luo Z, Liu J, Yang H, Mach RH, Kotzbauer PT, Tu Z. (2018). Design, synthesis, and in vitro evaluation of quinolinyl analogues for α-synuclein aggregation. Bioorg Med Chem Lett. [Epub ahead of print]. PubMed PMID: 29482941.
     
  2. Barclay AM, Dhavale DD, Courtney JM, Kotzbauer PT, Rienstra CM. (2018). Resonance assignments of an α-synuclein fibril prepared in Tris buffer at moderate ionic strength. Biomol NMR Assign. [Epub ahead of print]. PubMed PMID: 29476328.
  3. Dhavale DD, Tsai C, Bagchi DP, Engel LA, Sarezky J, Kotzbauer PT. (2017). A sensitive assay reveals structural requirements for α-synuclein fibril growth. J Biol Chem. 292(22):9034-9050. PubMed PMID: 28373279.

  4. Buddhala C, Campbell MC, Perlmutter JS, Kotzbauer PT. (2015). Correlation between decreased CSF α-synuclein and Aβ1-42 in Parkinson disease. Neurobiol Aging. 36(1):476-84. PubMed PMID: 25212463. 

  5. Campbell MC, Koller JM, Snyder AZ, Buddhala C, Kotzbauer PT, Perlmutter JS. (2015). CSF proteins and resting-state function connectivity in Parkinson's disease. Neurology. 84(24):2413-2421. PubMed PMID: 25979701.

  6. Kotzbauer PT, Cairns NJ, Campbell MC, Willis AW, Racette BA, Tabbal SD, Perlmutter JS. (2012). Pathologic accumulation of α-synuclein and Aβ in Parkinson disease patients with dementia. Arch Neurol. 69(10):1326-1331. PubMed PMID: 22825369.

  7. Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, Lee VM. (2004). Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation. Exp Neurol. 187(2):279-88. PubMed PMID: 15144854.